Life-threatening pediatric epilepsies like Dravet Syndrome (DS) are unresponsive to standard therapy. We will assess the efficacy of the Nav1.6-specific sodium channel blocker XEN-A in Scn1a+/- mice, a validated mouse genetic model of this devastating childhood epilepsy disorder. DS is caused by dominant, heterozygous loss- of-function mutations in the gene SCN1A, encoding brain sodium channel Nav1.1. Our mouse genetic model exhibits all facets of DS, including thermally induced seizures, spontaneous seizures, premature death, hyperactivity, severe cognitive impairment, and autistic-like behaviors. These manifestations of DS are caused by selectively impaired action potential firing in GABAergic inhibitory neurons in hippocampus and cerebral cortex, which alters the balance of excitation to inhibition in neural circuits in favor of excitation. DS mice provide a unique resource to study the effects of XEN-A on a naturally occurring intractable epilepsy. Nav1.6 is the primary sodium channel in excitatory neurons, where it drives repetitive firing. It is a prime target for next- generation antiepileptic drugs, but none have been tested in DS. As proof-of-principle, we made DS mice that were heterozygous for a loss-of-function mutation in Nav1.6. These mice were much less susceptible to seizures and premature death, supporting inhibition of Nav1.6 as a therapeutic strategy in DS. Drug discovery research has yielded next-generation Nav1.6 inhibitors that are highly selective among sodium channel types, in sharp contrast to the nonselectivity of traditional sodium channel blockers that are not effective in DS. We will test the efficacy of a next-generation Nav1.6 drug (XEN-A, Xenon Pharmaceuticals) in our mouse model of DS. We hypothesize that Nav1.6-selective inhibitors will have potent antiepileptic effects in DS mice by specifically inhibiting Nav1.6 in excitatory neurons in a voltage-dependent manner and will further have beneficial effects on hyperactivity, cognitive deficit, and autistic-like behavior by re-balancing excitation and inhibition. We will test XEN-A on thermally induced seizures, frequency and severity of spontaneous seizures and premature death, and cognitive and behavioral deficits, including hyperactivity, repetitive behaviors, impaired spatial learning and memory, and autistic-like behaviors. We will analyze seizure mechanisms in DS mice treated with XEN-A by electroencephalographic recording (EEG) and determine mechanism of action of XEN-A in electrophysiological studies of neurons in brain slices. Our results could transform treatment of pediatric epilepsies by identifying physiological mechanism(s) that render these seizures tractable and so permit development of improved therapeutic strategies for control of intractable seizures. Determination of the underlying mechanisms will provide a solid basis for the development of a new class of antiepileptic drugs to benefit pediatric epilepsies broadly and may help to better understand key physiological processes that can be targeted to control intractable seizures.